Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: Results of the CROSS study

OBJECTIVE:The increase in blood pressure that accompanies the obese state is almost invariably associated with alterations in metabolism (insulin resistance and dyslipidaemia) and the neurohumoral profile (activation of the renin-angiotensin system, sympathetic overactivity), which potentiate the cardiovascular risk associated with hypertension. However, debate remains as to the antihypertensive drug on which treatment of obesity-related hypertension should be based. The CROSS (Candesartan Role on Obesity and on Sympathetic System) study was undertaken to examine the antihypertensive, neuroadrenergic, and metabolic effects of an angiotensin II receptor blocker in comparison with a diuretic in obese hypertensive individuals. METHODS:In 127 obese hypertensive individuals aged 50.7 +/- 5.1 years (mean +/- SD), we measured clinic blood pressure, heart rate, plasma glucose, and insulin at rest and during an oral glucose load before and 12 weeks after treatment with either candesartan cilexetil (8-16 mg once daily) or hydrochlorothiazide (HCTZ, 25-50 mg once daily), administered orally in accordance with a double-blind, randomized, placebo-controlled, two-parallel-groups study design. Insulin sensitivity was expressed as insulin resistance index (IRI), calculated as the ratio of the area under the curve (AUC) for glucose to that for insulin. In a subgroup of patients, measurements also included direct microneurographic recording of muscle sympathetic nerve activity (MSNA) in the peroneal nerve. RESULTS:Candesartan cilexetil caused a significant (P < 0.01) reduction in both mean blood pressure (from 114.2 +/- 5.1 to 99.6 +/- 6.0 mmHg) and MSNA (from 51.0 +/- 12.3 to 40.4 +/- 12.5 bursts per 100 heart beats), and a significant (P < 0.02) increase in insulin sensitivity (AUC IRI: from -23.2 +/- 22.1 to -17.6 +/- 12.2). In contrast, HCTZ did not significantly affect MSNA and worsened insulin sensitivity, while achieving blood pressure reductions similar to those produced by candesartan cilexetil. CONCLUSIONS: These data provide evidence that, in obese hypertensive individuals, treatment with candesartan cilexetil has an antihypertensive effect similar to that of HCTZ. Unlike diuretic treatment, however, treatment with candesartan cilexetil improves insulin sensitivity and exerts sympathoinhibitory effects.